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Introduction

The unique shapes woven by protein chains enable proteins to adopt many distinct roles in living things such as channels, sensors, and transporters. They can also act as catalysts for chemical reactions, including the capacity to catalyse the degradation of other protein chains. Snake venom metalloproteinase (SVMP) is a protein that breaks down other proteins, specifically extracellular matrix (ECM) and plasma proteins such as fibrinogen (coagulation factor I). Protein degradation by SVMP causes tissue damage in blood vessels and disrupts our body’s normal blood clotting processes.

Snake venoms are a complex mixture of 20 to 100 or more different proteins or peptides (shorter protein chains), each playing a role in the harmful effects experienced by snakebite victims (2). This month’s artwork is inspired by the parallel of a slithering, coiling snake and the curling, weaving of a single protein chain found in a SVMP from the Taiwan Habu, which is also called the brown-spotted pit viper (Protobothrops mucrosquamatus; historically also referred to as Trimeresurus mucrosquamatus) (Fig 1). This snake is the most common cause of death or injury by snakebite in Taiwan and is found throughout south and southeastern Asia. The SVMP protein is colored with the chain starting with lighter colors at the N-terminus and gradually changing to darker colors toward the C-terminus (Fig. 2).

 

 

Of the 4000+ species of snake, ~600  are venomous, with a subset that has venom powerful enough to kill (3). Contributing to the more deadly toxicity of snake venom is the presence of the protein SVMP.

Venomous snakes belong to either the Elapidae family, which includes species like the Black Mamba and King Cobra, or the Viperidae family, which includes rattlesnakes, vipers, and adders. For rattlesnakes, vipers, and the majority of the Viperidae family members, SVMP is the most predominant venom protein by concentration. Of the protein content in venom, 33% is SVMP, when considering 117 species from the Viperidae family, whereas a similar analysis indicates 5% of protein content is SVMP in venom from snakes in the Elapidae family (2).

A common protein fold for human tissue and blood vessel degradation

All SVMP’s share a common region that requires the presence of a metal ion (purple sphere in Fig 2 and Fig 3) to be able to catalyse protein degeneration. This signature protein fold / domain shared between all SVMPs can also be found in non-snake proteins known to degrade protein, such as human collagenases. This domain, with similarities in protein sequence and secondary structure elements (Fig 3), has 5 stranded β-sheet surrounded by α-helices (1, 4). Proteins such as SVMP, which contain this domain are part of a protein superfamily named collagenase (). Binding to zinc is a common feature of the collagenase superfamily with a Zn2+ binding motif of HEXXHXXGXXH identified, where X could be any amino acid (5). 

Human collagenases participate in our body’s natural processes of tissue remodeling and repair by breaking down the ECM protein collagen and enabling cell growth. Broadly, SVMP and collagenases can be classed as metalloproteinases, proteins that degrade protein chains and require a metal. SVMP and collagenases are also part of a collection of proteins referred to as matrix metalloproteinases (MMPs), which degrade a variety of ECM proteins and require the removal of a peptide to become active.

 

Understanding blood clotting, tissue repair, and more

The way SVMP targets specific proteins differs between the three classes. Class P-I SVMPs are composed of the matrix metalloproteinase domain only (Fig 2 and Fig 3), whereas class P-II and class P-III have additional folded regions/domains. These additional domains are the disintegrin-like and cysteine-rich domains (4). The disintegrin-like domain can impair normal clotting by binding a specific receptor found on the surface of the human blood cells called platelets. In normal blood clotting this receptor or intergin is bound by human fibrinogen as part of normal platelet aggregation in response to injury (6). Certain snakes have class P-II SVMP’s that have a cleavage site within their protein chain, so that the disintegrin-like domain that targets platelets is cleaved into a separate protein and thus can function independently of the SVMP’s metalloprotease domain (4). The disintegrin-like domain in combination with the metalloproteinase domain directs the protein degrading activity of SVMP to fibrinogen approaching platelets to form blood clots such as found in a SVMP class P-III protein (Fig 4) from the sharp-nosed viper or Chinese moccasin (Deinagkistrodon acutus; historically referred to as Agkistrodon acutus).

 

Class P-II and P-III SVMP can be considered related to the proteins in the ‘A Disintegrin And Metalloproteinase� (ADAM) family, which includes 20+ human membrane-anchored protein degrading proteins that have both metalloproteinase and alter cell behaviour through modifications to the cell surface and the ECM. ADAM proteins are among those enabling a normal balance between cell growth and programmed cell death. An imbalance in these processes could mean appropriate tissue repair does not occur, thus the lack of expression of certain human ADAM proteins is linked to an increased risk of heart attacks in animal models (6).

Understanding how snake venom metalloproteinases (SVMPs) work provides insights into blood clotting and tissue repair, and more broadly develops understanding and new potential treatments for cardiovascular disease (6). This is in part due to how protein chains are ‘coiled� into a similar 3D shape for the snake venom component and the human proteins involved in blood clotting and tissue repair. Moreover, the function SVMPs have in snake venom means they are potential starting points for therapeutics to treat diseases related to abnormal blood clot formation (4).

Did you know?

1. There are drugs currently utilized to treat cardiovascular disease that have come from research on protein and peptide components in snake venom. Examples included the drugs captopril and eptifibatide (2).
2. Coagulopathy, or the lack of blood’s ability to form a clot, can be an important clinical indicator of the need for antivenom after a snakebite (7).

 

Genevieve Evans

 

About the artwork

Katie, aged 15, is a student at The Stephen Perse Foundation in Cambridge, UK. Fascinated by the extraordinary and dangerous efficacy of snake venom, Katie explored snake venom metalloproteinases (SVMPs) and expressed her understanding through her artwork by using various techniques like washes, sketching, and stippling to create depth, tone and contrast. 

View the artwork in the .

Structures mentioned in this article

Link to the PDB IDs for the entries in the images in this publication

• SVMP class P-I (PDB ID 4j4m)
• Human collagenase (PDB ID 2oy4)
• SVMP class P-III (PDB ID 3hdb)

Structure sources

• PDB ID 4j4m:
  
• PDB ID 2oy4:
  
• PDB ID 3hdb:
  

More structures to explore

• SVMP P-II from brown-spotted pit viper with & without peptide-like inhibitors
  • PDB ID 1kuf, PDB ID 1kug, PDB ID 1kui, PDB ID 1kuk 
  • Structural comparison on PDBe-KB pages:
    Zinc metalloproteinase/disintegrin 

List of abbreviations

SVMP - Snake Venom Metalloproteinase 

ECM - Extracellular Matrix

ADAM - A Disintegrin And Metalloproteinase (protein family)

MMP - Matrix Metalloproteinase

Sources / Further reading

Inspiration for artwork

Review on snake venom components

The Reptile Database

3. Uetz, P. (editor), The Reptile Database, , accessed Dec 1, 2024.

More on the history of the Reptile Database:

Reviews on metalloproteinases from snakes and humans

WHO advice on the treatment for a snakebite from a venomous snake